1. Filed of Invention
This invention relates to triphenylpropanamide compounds which are useful in treating inflammations but which do not demonstrate the side effects normally associated with other anti-inflammatory treatments such as glucocorticoids This invention also relates to methods for making and using the compounds of the invention.
2. Prior Art
Glucocorticoids are the only agents which reduce all the symptoms that are manifested in chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, inflammatory bowel disease, pneumonia bronchial asthma, hematological disorders, dermatitis and eczema. Glucocorticoids also reduce immunological response in organ transplants. The undesired side effects of these agents include hypertension, atherosclerosis, diabetes, hyperglycemia, bone Fining and electrolyte imbalance.
Mechanistically, glucocorticoids bind to the glucocorticoid receptor (GR) on the surface of leukocytes and the resulting glucocorticoid -GR complex migrates into Fe cell nucleus. There, the complex interacts with transcription factor AP-1 (activating protein-1), inhibiting its induction of genes that produce inflammatory cytokines and collagenase, thereby repressing the inflammatory process. However, the complex also activates GRE (glucocorticoid response element), a transcriptional activator of genes which are responsible for the undesirable side effects mentioned heretofore. The most desirable anti-inflammatory medication would inhibit AP-1 without activating GRE.
Steroids, such as dexamethasone and prednisone have been found to exhibit potent antiinflammatory activity, but also exhibit the previously-mentioned side effects.
Heretofore there has been no antiinflammatory agent found which does not cause side effects. Thus, new chemical agents are needed which would have the desired antiinflammatory effect without causing the side effects mentioned above.
Prior art compounds which relate to the triphenylcydopropyl and triphenylpropyl compounds of the invention are as follows: U.S. Pat. No. 3,941,833 (Gognaco) describes certain amino derivatives of 2,2-diaryl-cyclopropane. They are described as being useful for the treatment of disorders of the cardiovascular system. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
Gilbert, et al. in J. Med. Chem. 1983, 26, 693-699 report triphenylpropylidene amines and nitriles as inhibitors of prostaglandin synthetase
Blank et al. in J. Med. Chem. 1969, 12, 873-876 describe the inhibition by 2,3,3-triphenylpropylamines of the biosynthesis of aldosterone without altering deoxycorticosterone or corticosterone levels.
Schultz et al. in J. Med. Chem. 1967, 10, 717-724 describe diphenylpropanamides which are hypocholesteremic in rats and inhibit penicillin excretion in dogs.
Burch et al. in Proc. Natl. Acad. Sci. USA 1991, 88, 355-359 describe fluorenyl propanamides which inhibit localized inflammatory reactions in mice.
German Patent No. 2,726,993 (Gognaco) describes 1-substituted 2,2-diphenylcydopropanes. The patent indicates that they are useful as vasodilators and blood pressure lowering agents. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
Belgian patent No. BE 855689 (Hexachemie S. A. Fr.) describes 2,2-diphenylcyclopropylmethylamides with vasodilator activity.
Precigoux, et al. describe the compound 4,4xe2x80x2-(3Acetemido-2-phenylpropylidene) diphenol diacetate in Acta Crystallogr., Sect. C. Cryst. Struct. Commun., C41 (8), 1985, pp. 1244-1246.
Falkenstein et al. describe certain phenylaziridine compounds in xe2x80x9cSingle electron transfer versus nucleophilic ring opening in reactions of cis-trans pairs of activated 2-phenylaziridines. Strong influence of nitrogen pyramid for N-benzoylaziridinesxe2x80x9d, J. Org. Chem., 1993, 58, pp. 7377-7381.
Stamm et al. describe other aziridines in xe2x80x9cReactions with aziridines. 53. Arene hydrides. 9. Intermediate substitution in the formation of a benzylic anion by an aromatic radical anion as observed with 1-benzoyl-2-phenylaziridine.xe2x80x9d Chem. Ber., 1990, 123, pp. 2227-2230. Stamm et al. also described related aziridine structures in xe2x80x9cReductive ring opening of N-benzoylaziridine by anthracene hydride (anion of 9,10-dihydroanthracene) via base-induced fragmentation of the intermediate carbonyl adduct.xe2x80x9d J. Org. Chem., 1989, 54, pp. 1603-1607. However, none of these publications describe the structures of this invention nor do they indicate that such compounds would be useful in treating inflammation.
Therefore, it is an object of this invention to provide one or more compounds capable of treating inflammatory diseases.
It is a further object of this invention to provide compounds capable of treating inflammatory diseases without causing side effects similar to those caused by glucocorticoids.
It is yet another object of this invention to provide a method of making compounds for treating inflammatory diseases.
Another object of this invention is to provide a method of treating inflammatory diseases in mammals by administration of the compounds of this invention.
This invention relates to novel non-steroidal small molecule organic compounds that exhibit the beneficial therapeutic properties of glucocorticoids, that may be free of glucocorticoid-like side effects, and which may have a high affinity for the human glucocorticoid receptor (hGR). The compounds of this invention have the following structure (I): 
wherein X, R1, R2, R3, R4, R5, W, Y and Z are as defined hereinafter. These compounds are useful in treating inflammatory diseases in humans and other mammals. The compounds of the present invention may also be useful in the treatment of other disorders, such as chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, use as immunosuppressants in organ transplant, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. The present invention is also directed to pharmaceutical compositions containing the compounds of formula I and methods of treating inflammation and other conditions employing such compounds.
As used herein unless otherwise noted, alkyl and alkoxy, whether used along or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Of course, if the alkyl or alkoxy substituent is branched there must be at least three carbon atoms in the group.
The term xe2x80x9carylxe2x80x9d as used herein along or in combination with other terms indicates aromatic hydrocarbon groups such as phenyl or naphthyl. The term heteroaryl means aromatic groups, incorporating as part of the aromatic ring, 1 or 2 hetero atoms selected from any of S, O, or N. With reference to substituents, the term xe2x80x9cindependentlyxe2x80x9d means that when more than one of such substituent is possible such substituents may be the same or different from each other.